Role of IL-18 in adipose tissue remodeling and metabolic dysfunction.

BACKGROUND/OBJECTIVES: Proinflammatory cytokines are increased in obese adipose tissue, including inflammasome key masters. Conversely, IL-18 protects against obesity and metabolic dysfunction. We focused on the IL-18 effect in controlling adipose tissue remodeling and metabolism. MATERIALS/SUBJECTS AND METHODS: We used C57BL/6 wild-type (WT) and interleukine-18 deficient (IL-18-/-) male mice fed a chow diet and samples from bariatric surgery patients. RESULTS: IL-18-/- mice showed increased adiposity and proinflammatory cytokine levels in adipose tissue, leading to glucose intolerance. IL-18 was widely secreted by stromal vascular fraction but not adipocytes from mice's fatty tissue. Chimeric model experiments indicated that IL-18 controls adipose tissue expansion through its presence in tissues other than bone marrow. However, IL-18 maintains glucose homeostasis when present in bone marrow cells. In humans with obesity, IL-18 expression in omental tissue was not correlated with BMI or body fat mass but negatively correlated with IRS1, GLUT-4, adiponectin, and PPARy expression. Also, the IL-18RAP receptor was negatively correlated with IL-18 expression. CONCLUSIONS: IL-18 signaling may control adipose tissue expansion and glucose metabolism, as its absence leads to spontaneous obesity and glucose intolerance in mice. We suggest that resistance to IL-18 signaling may be linked with worse glucose metabolism in humans with obesity.

Cotadutide effect in liver and adipose tissue in obese mice.

Obesity, adipose tissue inflammation, and nonalcoholic fatty liver disease (NAFLD) are associated with insulin resistance and type 2 diabetes (T2D). Cotadutide is a dual agonist GLP-1/glucagon, currently in a preclinical study phase 2 that presents an anti-obesity effect. Diet-induced obese (DIO) C57BL/6 mice were treated for 4 weeks with cotadutide (30 nm/kg once a day at 14:00 h). The study focused on epididymal white adipose tissue (eWAT), liver (NAFLD), inflammation, lipid metabolism, AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) pathways, and the endoplasmic reticulum (ER) stress. As a result, cotadutide controlled weight gain, glucose intolerance, and insulin resistance and showed beneficial effects on plasma markers in DIO mice (triacylglycerol, total cholesterol, alanine aminotransferase, and aspartate aminotransferase, leptin, adiponectin, monocyte chemoattractant protein-1, resistin, interleukin-6, tumor necrosis factor-alpha). Also, cotadutide lessened liver fat accumulation, eWAT proinflammatory markers, and ER stress. In addition, cotadutide improved lipid metabolism genes in eWAT, fatty acid synthase, peroxisome proliferator-activated receptor gamma and mitigates adipocyte hypertrophy and apoptosis. Furthermore, the effects of cotadutide were related to liver AMPK/mTOR pathway and ER stress. In conclusion, cotadutide induces weight loss and treats glucose intolerance and insulin resistance in DIO mice. In addition, cotadutide shows beneficial effects on liver lipid metabolism, mitigating steatosis, inflammation, and ER stress. Besides, in adipocytes, cotadutide decreases hypertrophy and reduces apoptosis. These actions rescuing the AMPK and mTOR pathway, improving lipid metabolism, and lessening NAFLD, inflammation, and ER stress in both eWAT and liver of DIO mice indicate cotadutide as a potentially new pharmacological treatment for T2D and associated obesity.

Maternal obesity damages the median eminence blood-brain barrier structure and function in the progeny: the beneficial impact of cross-fostering by lean mothers.

Maternal obesity is an important risk factor for obesity, cardiovascular, and metabolic diseases in the offspring. Studies have shown that it leads to hypothalamic inflammation in the progeny, affecting the function of neurons regulating food intake and energy expenditure. In adult mice fed a high-fat diet, one of the hypothalamic abnormalities that contribute to the development of obesity is the damage of the blood-brain barrier (BBB) at the median eminence-arcuate nucleus (ME-ARC) interface; however, how the hypothalamic BBB is affected in the offspring of obese mothers requires further investigation. Here, we used confocal and transmission electron microscopy, transcript expression analysis, glucose tolerance testing, and a cross-fostering intervention to determine the impact of maternal obesity and breastfeeding on BBB integrity at the ME-ARC interface. The offspring of obese mothers were born smaller; conversely, at weaning, they presented larger body mass and glucose intolerance. In addition, maternal obesity-induced structural and functional damage of the offspring's ME-ARC BBB. By a cross-fostering intervention, some of the defects in barrier integrity and metabolism seen during development in an obesogenic diet were recovered. The offspring of obese dams breastfed by lean dams presented a reduction of body mass and glucose intolerance as compared to the offspring continuously exposed to an obesogenic environment during intrauterine and perinatal life; this was accompanied by partial recovery of the anatomical structure of the ME-ARC interface, and by the normalization of transcript expression of genes coding for hypothalamic neurotransmitters involved in energy balance and BBB integrity. Thus, maternal obesity promotes structural and functional damage of the hypothalamic BBB, which is, in part, reverted by lactation by lean mothers.NEW & NOTEWORTHY Maternal dietary habits directly influence offspring health. In this study, we aimed at determining the impact of maternal obesity on BBB integrity. We show that DIO offspring presented a leakier ME-BBB, accompanied by changes in the expression of transcripts encoding for endothelial and tanycytic proteins, as well as of hypothalamic neuropeptides. Breastfeeding in lean dams was sufficient to protect the offspring from ME-BBB disruption, providing a preventive strategy of nutritional intervention during early life.

Enriched functional milk fat ameliorates glucose intolerance and triacylglycerol accumulation in skeletal muscle of rats fed high-fat diets.

PURPOSE: We examined the effect of a functional milk fat (FMF) on the glucose metabolism and its association with the intramuscular triacylglycerol (TAG) content in rats fed high-fat diets. METHODS: Male Wistar rats were fed for 60 days with S7 (soybean oil 7%), S30 (soybean oil 30%), MF30 (soybean oil 3% + milk fat 27%), or FMF30 (soybean oil 3% + FMF 27%) diets. An oral glucose tolerance test was performed. The levels of key metabolites in gastrocnemius muscle and mRNA levels of genes involved in glucose and lipid metabolism in muscle, epididymal white adipose tissue (EWAT), and serum were assessed. RESULTS: The S30 diet induced glucose intolerance and led to TAG, citrate, and glucose accumulation in muscle. Moreover, we observed a downregulation of uncoupling proteins (Ucp2 and Ucp3) and insulin receptor substrate-1 (Irs1) genes, lower carnitine palmitoyl transferase-1b (CPT-1b), and phosphofructokinase-1 (PFK1) activities in muscle and lower expression of adiponectin (Adipoq) in EWAT. The FMF30 diet ameliorated the glucose intolerance and normalized the glucose and TAG levels in muscle, preventing the accumulation of citrate and enhancing glucose utilization by the PFK1. The beneficial effects might also be related to the higher expression of Adipoq in EWAT, its receptor in muscle (Adipor1), and the expression of Ucp2, Ucp3, and Irs1 in muscle, restoring the alterations observed with the S30 diet. CONCLUSIONS: FMF30 modulated key genes involved in glucose and lipid metabolism in skeletal muscle, improving the glucose utilization and preventing TAG, glucose, and citrate accumulation.

Severe Hyperprolactinemia Promotes Brown Adipose Tissue Whitening and Aggravates High Fat Diet Induced Metabolic Imbalance.

Background: The association of high serum prolactin and increased body weight is positive but controversial, therefore we hypothesized that additional factors such as diets and the impact of prolactin on brown adipose tissue may condition its metabolic effects. Methods: We used LacDrd2KO females with lifelong severe hyperprolactinemia due dopamine-D2 receptor deletion from lactotropes, and slow onset of metabolic disturbances, and compared them to their respective controls (Drd2 loxP/loxP ). Food intake, and binge eating was evaluated. We then challenged mice with a High Fat (HFD) or a Control Diet (CD) for 8 weeks, beginning at 3 months of age, when no differences in body weight are found between genotypes. At the end of the protocol brown and white adipose tissues were weighed, and thermogenic and lipogenic markers studied, using real time PCR (Ucp1, Cidea, Pgc1a, Lpl, adiponectin, Prlr) or immunohistochemistry (UCP1). Histochemical analysis of brown adipose tissue, and glucose tolerance tests were performed. Results: Hyperprolactinemic mice had increased food intake and binge eating behavior. Metabolic effects induced by a HFD were exacerbated in lacDrd2KO mice. Hyperprolactinemia aggravated HFD-induced body weight gain and glucose intolerance. In brown adipose tissue pronounced cellular whitening as well as decreased expression of the thermogenic markers Ucp1 and Pgc1a were observed in response to high prolactin levels, regardless of the diet, and furthermore, hyperprolactinemia potentiated the decrease in Cidea mRNA expression induced by HFD. In subcutaneous white adipose tissue hyperprolactinemia synergistically increased tissue weight, while decreasing Prlr, Adiponectin and Lpl mRNA levels regardless of the diet. Conclusions: Pathological hyperprolactinemia has a strong impact in brown adipose tissue, lowering thermogenic markers and evoking tissue whitening. Furthermore, it modifies lipogenic markers in subcutaneous white adipose, and aggravates HFD-induced glucose intolerance and Cidea decrease. Therefore, severe high prolactin levels may target BAT function, and furthermore represent an adjuvant player in the development of obesity induced by high fat diets.

Lactation overnutrition-induced obesity impairs effects of exogenous corticosterone on energy homeostasis and hypothalamic-pituitary-adrenal axis in male rats.

AIMS: Litter size reduction on the first days of life results in increased body weight and adiposity, with higher levels of circulating glucocorticoids. Obese rodents are more sensitive to the anabolic effects of glucocorticoids and less responsive to glucocorticoids feedback on hypothalamic-pituitary-adrenal (HPA) axis. This study aimed to evaluate effects of the treatment with corticosterone on metabolic responses and HPA axis in adult male rats reared in small litters. MAIN METHODS: From postnatal day (PND) 60 to 88, adult male rats of normal (NL- 10 pups/dam) and small (SL- 3 pups/dam) litters received oral treatment with Corticosterone (CORT-15 mg/L) in the drinking water or no treatment, composing the four experimental groups (NL-water; NL-CORT; SL-water and SL-CORT), for the evaluation of energy homeostasis and HPA axis. KEY FINDINGS: Male rats of SL-water group presented on PND88: glucose intolerance, higher adiposity, plasma triglycerides, free fatty acids, total and low-density lipoprotein (LDL) cholesterol and corticosterone. SL-water animals showed increased mRNA of corticotrophin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN) and proopiomelanocortin (POMC) in the pituitary, with decreased mRNA expression of PVN mineralocorticoid receptor. NL-CORT animals presented glucose intolerance, increased body weight, food intake, total and LDL cholesterol. Glucocorticoid treatment reduced corticosterone levels and adrenal cortex thickness in NL group, associated with increased mRNA of PVN CRH and pituitary POMC, without effects on SL animals. SIGNIFICANCE: Lactation overnutrition promotes hyperreactivity of HPA axis and reduces the responsiveness to glucocorticoids effects on energy balance and negative feedback of HPA axis in adult male rats.

Siolmatra brasiliensis stem extract ameliorates antioxidant defenses and mitigates glycoxidative stress in mice with high-fat diet-induced obesity.

BACKGROUND: Obesity is accompanied by insulin resistance and glucose intolerance, which favor the onset of complications related to oxidative stress. The aim of this study was to investigate the effects and underlying mechanisms of hydroethanolic extract from Siolmatra brasiliensis stems on insulin resistance, glucose intolerance, advanced glycation end product (AGE) formation, and oxidative stress in mice with induced obesity. METHODS: C57BL-6 J mice were fed a high-fat diet for 14 weeks and treated with 125 or 250 mg/kg S. brasiliensis extract during the last 7 weeks. The study assessed glucose tolerance and insulin sensitivity, lipid profile, plasma levels of thiobarbituric acid reactive substances (TBARS, biomarkers of oxidative damage), fluorescent AGEs (biomarkers of advanced glycation), and paraoxonase 1 (PON1) activity (antioxidant enzyme). The activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in the liver and kidneys were also investigated. RESULTS: Siolmatra brasiliensis extract had antiobesogenic effects; improved insulin sensitivity and glucose tolerance; decreased the total plasma cholesterol levels; decreased the levels of glycoxidative stress biomarkers, including AGEs (plasma, liver, kidneys) and TBARS (liver, kidneys); and also improved endogenous antioxidant defenses by increasing the activities of PON1 (plasma), SOD (kidneys), CAT (liver, kidneys), and GSH-Px (kidneys). CONCLUSION: This study expands on our knowledge about the pharmacological properties of S. brasiliensis and substantiates the potential of this plant species to be used as a complementary therapeutic agent to alleviate the metabolic dysfunctions resulting from dyslipidemia and glycoxidative stress.

Dietary citrate acutely induces insulin resistance and markers of liver inflammation in mice.

Citrate is widely used as a food additive being part of virtually all processed foods. Although considered inert by most of the regulatory agencies in the world, plasma citrate has been proposed to play immunometabolic functions in multiple tissues through altering a plethora of cellular pathways. Here, we used a short-term alimentary intervention (24 hours) with standard chow supplemented with citrate in amount corresponding to that found in processed foods to evaluate its effects on glucose homeostasis and liver physiology in C57BL/6J mice. Animals supplemented with dietary citrate showed glucose intolerance and insulin resistance as revealed by glucose and insulin tolerance tests. Moreover, animals supplemented with citrate in their food displayed fed and fasted hyperinsulinemia and enhanced insulin secretion during an oral glucose tolerance test. Citrate treatment also amplified glucose-induced insulin secretion in vitro in INS1-E cells. Citrate supplemented animals had increased liver PKCα activity and altered phosphorylation at serine or threonine residues of components of insulin signaling including IRS-1, Akt, GSK-3 and FoxO1. Furthermore, citrate supplementation enhanced the hepatic expression of lipogenic genes suggesting increased de novo lipogenesis, a finding that was reproduced after citrate treatment of hepatic FAO cells. Finally, liver inflammation markers were higher in citrate supplemented animals. Overall, the results demonstrate that dietary citrate supplementation in mice causes hyperinsulinemia and insulin resistance both in vivo and in vitro, and therefore call for a note of caution on the use of citrate as a food additive given its potential role in metabolic dysregulation.

Animal models of gestational diabetes: characteristics and consequences to the brain and behavior of the offspring.

Gestational diabetes (GD) is the glucose intolerance that occurs during pregnancy. Mothers who develop diabetes during gestation are at increased risk of developing type 2 diabetes mellitus (T2DM) later in life, and the risk of adverse fetal and neonatal outcomes are also increased as a function of maternal hyperglycemia. Infants who are exposed to fetal hyperglycemia show an increased risk of becoming obese and developing T2DM later in life. Due to the need of new research on this field, and the difficulty of performing studies in human brain, studies using experimental models are necessary to suggest possible ways to avoid or inhibit offspring brain damage or harmful metabolic alterations. Here, it was made a review about the characteristics of the main animal models of GD, and what are the consequences to the brain and behavior of the offspring. In many experimental models, either by pharmacological induction, diet manipulation, or in the use of transgenic animals, glycemic conditions are severe. S961, a selective insulin receptor antagonist, revealed an increased fasting blood glucose level and glucose intolerance during mid-gestation, which returned to basal levels postpartum in mice. GD contributes to offspring neuroinflammation, influences neuronal distribution in central nervous system (CNS), and apoptosis during embryogenesis, which in turn may contribute to changes in behavior and memory in adult life and aging. The usage of animal models to study GD allows to examine extensively the characteristics of this condition, the molecular mechanisms involved and the consequences to the brain and behavior of the offspring.

Insulin resistance may be misdiagnosed by HOMA-IR in adults with greater fat-free mass: the ELSA-Brasil Study.

AIMS: Conflicting results have been reported on the association of fat-free mass (FFM) and insulin resistance (IR). This study sought to test the association of FFM and IR by indexing FFM to avoid collinearity with fat mass. METHODS: This cross-sectional study comprised 11,284 volunteers, aged 38-79 years. Body composition was assessed by multi-frequency bioelectrical impedance. FFM indexed to body surface area (FFMbsa) was calculated. IR and impaired glucose tolerance (IGT) were estimated with homeostatic model assessment of insulin resistance index (HOMA-IR) and 2-h oral glucose tolerance test (2h-OGTT), respectively. RESULTS: Percent body fat decreased from the 1st to the 5th quintile of FFMbsa in both women (Eta2 = 0.166) and men (Eta2 = 0.133). In women, fasting insulin (Eta2 = 0.002), glucose (Eta2 = 0.006), and HOMA-IR (Eta2 = 0.007) increased slightly, but 2-h plasma glucose (2-h PG) was similar across the quintiles of FFMbsa. In men, fasting insulin and HOMA-IR were similar across the quintiles of FFMbsa, whereas fasting glucose increased slightly (Eta2 = 0.002) and 2-h PG decreased (Eta2 = 0.005) toward the highest quintile of FFMbsa. The higher the odds ratio for IR, the greater the FFMbsa in both sexes. Differently, FFMbsa did not affect the odds of IGT in women, while in men the odds ratio for IGT was lower in the 5th quintile compared with the 1st quintile of FFMbsa. CONCLUSIONS: Higher odds of IR associated with greater FFMbsa contrasted with lower odds of IGT associated with greater FFMbsa. IR may be misdiagnosed by HOMA-IR in adults with greater fat-free mass.

Eplerenone Implantation Improved Adipose Dysfunction Averting RAAS Activation and Cell Division.

Introduction: Mineralocorticoid receptor (MR) activation within adipose tissue, triggers inflammation and metabolic syndrome development. The pharmacological blockade of MR provides beneficial effects for adipose tissue. Our study evaluates the impact of eplerenone implantation upon obesity. Experimental approach: A group of mice with implanted placebo pellets were fed using two types of diet, a normal (ND) or a high fat (HFD) diet. Additionally, a group of mice fed HFD were implanted with an eplerenone pellet. Metabolic and biochemical parameters were assessed in each animal group. Adipocyte size and lipid accumulation were investigated in the liver and adipose tissue. We evaluated the components of renin-angiotensin-aldosterone system (RAAS) locally in adipose tissue. Key results: Eplerenone reduced HFD-induced body weight gain, fasting glucose levels, fat accumulation, HFD-induced adipocyte size and liver lipid accumulation and improved glucose tolerance. In the adipose tissue, HFD significantly increased the mRNA levels of the RAAS molecules relative to the ND group. Eplerenone lowered RAAS mRNA levels, components of lipid metabolism and markers of inflammation in HFD-fed animals. Conclusion: MR antagonism with eplerenone diminishes insulin resistance that is related to obesity partly via a reduction of RAAS activation, inflammatory progression and cytokines induction. This suggests that eplerenone should be further studied as a therapeutic option for obesity and overweight.

Intermediate hyperglycaemia and 10-year mortality in resource-constrained settings: the PERU MIGRANT Study.

AIM: To determine whether intermediate hyperglycaemia, defined by fasting plasma glucose and HbA1c criteria, is associated with mortality in a 10-year cohort of people in a Latin American country. METHODS: Analysis of the PERU MIGRANT Study was conducted in three different population groups (rural, rural-to-urban migrant, and urban). The baseline assessment was conducted in 2007/2008, with follow-up assessment in 2018. The outcome was all-cause mortality, and the exposure was intermediate hyperglycaemia, using three definitions: (1) impaired fasting glucose, defined according to American Diabetes Association criteria [fasting plasma glucose 5.6-6.9 mmol/l (100-125 mg/dl)]; (2) intermediate hyperglycaemia defined according to American Diabetes Association criteria [HbA1c levels 39-46 mmol/mol (5.7-6.4%)]; and (3) intermediate hyperglycaemia defined according to the International Expert Committee criteria [HbA1c levels 42-46 mmol/mol (6.0-6.4%)]. Crude and adjusted hazard ratios and 95% CIs were estimated using Cox proportional hazard models. RESULTS: At baseline, the mean (sd) age of the study population was 47.8 (11.9) years and 52.5% of the cohort were women. The study cohort was divided into population groups as follows: 207 people (20.0%) in the rural population group, 583 (59.7%) in the rural-to-urban migrant group and 198 (20.3%) in the urban population group. The prevalence of intermediate hyperglycaemia was: 6%, 12.9% and 38.5% according to the American Diabetes Association impaired fasting glucose definition, the International Expert Committee HbA1c -based definition and the American Diabetes Association HbA1c -based definition, respectively, and the mortality rate after 10 years was 63/976 (7%). Intermediate hyperglycaemia was associated with all-cause mortality using the HbA1c -based definitions in the crude models [hazard ratios 2.82 (95% CI 1.59-4.99) according to the American Diabetes Association and 2.92 (95% CI 1.62-5.28) according to the International Expert Committee], whereas American Diabetes Association-defined impaired fasting glucose was not [hazard ratio 0.84 (95% CI 0.26-2.68)]. In the adjusted model, however, only the American Diabetes Association HbA1c -based definition was associated with all-cause mortality [hazard ratio 1.91 (95% CI 1.03-3.53)], whereas the International Expert Committee HbA1c -based and American Diabetes Association impaired fasting glucose-based definitions were not [hazard ratios 1.42 (95% CI 0.75-2.68) and 1.09 (95% CI 0.33-3.63), respectively]. CONCLUSIONS: Intermediate hyperglycaemia defined using the American Diabetes Association HbA1c criteria was associated with an elevated mortality rate after 10 years in a cohort from Peru. HbA1c appears to be a factor associated with mortality in this Peruvian population.

Chronic kidney disease in patients with non-alcoholic fatty liver disease: What the Hepatologist should know?

The association of non-alcoholic fatty liver disease (NAFLD) with several other diseases has gained increased interest during the recent years. Among them, the association with chronic kidney disease (CKD) has emerged as an important one regarding both its prevalence and significance. The early recognition of this association is important for the prognosis of patients with NAFLD and CKD. Apart from early diagnosis, the accurate assessment of renal function is also crucial in the clinical practice of hepatologists. Several methods have been used in the literature for the evaluation of kidney function in patients with NAFLD up to now. In this respect, calculators (or formulas) for the estimation of Glomerular Filtration Rate (eGFR) and Albumin to Creatinine Ratio (ACR) are simple, practical and easily available methods for this purpose. The aim of this review is to report on the epidemiology and pathophysiology of the relationship between NAFLD and CKD and to describe the different methods of kidney function assessment in patients with NAFLD. The collection of all relevant data regarding this association will provide hepatologists with pertinent knowledge on this topic and allow them to use the most accurate methods for the assessment of kidney function in these patients in their clinical practice.

Angiotensin II type 2 receptor mediates high fat diet-induced cardiomyocyte hypertrophy and hypercholesterolemia.

Obesity is the major risk factor for several cardiovascular and metabolic disorders. Previous studies reported that deletion of Angiotensin II type 2 receptor (AT2R) protects against metabolic dysfunctions induced by high fat (HF) diet. However, the role of AT2R in obesity-induced cardiac hypertrophy remains unclear. Male AT2R knockout (AT2RKO) and wild type (AT2RWT) mice were fed with control or HF diet for 10 weeks. HF diet increased cardiac expression of AT2R in obese mice. Deletion of AT2R did not affect body weight gain, glucose intolerance and fat mass gain induced by HF feeding. However, loss of AT2R prevented HF diet-induced hypercholesterolemia and cardiac remodeling. Mechanistically, we found that pharmacological inhibition or knockdown of AT2R prevented leptin-induced cardiomyocyte hypertrophy in vitro. Collectively, our results suggest that AT2R is involved in obesity-induced cardiac hypertrophy.

Central growth hormone action regulates metabolism during pregnancy.

The maternal organism undergoes numerous metabolic adaptations to become prepared for the demands associated with the coming offspring. These metabolic adaptations involve changes induced by several hormones that act at multiple levels, ultimately influencing energy and glucose homeostasis during pregnancy and lactation. Previous studies have shown that central growth hormone (GH) action modulates glucose and energy homeostasis. However, whether central GH action regulates metabolism during pregnancy and lactation is still unknown. In the present study, we generated mice carrying ablation of GH receptor (GHR) in agouti-related protein (AgRP)-expressing neurons, in leptin receptor (LepR)-expressing cells or in the entire brain to investigate the role played by central GH action during pregnancy and lactation. AgRP-specific GHR ablation led to minor metabolic changes during pregnancy and lactation. However, while brain-specific GHR ablation reduced food intake and body adiposity during gestation, LepR GHR knockout (KO) mice exhibited increased leptin responsiveness in the ventromedial nucleus of the hypothalamus during late pregnancy, although their offspring showed reduced growth rate. Additionally, both Brain GHR KO and LepR GHR KO mice had lower glucose tolerance and glucose-stimulated insulin secretion during pregnancy, despite presenting increased insulin sensitivity, compared with control pregnant animals. Our findings revealed that during pregnancy central GH action regulates food intake, fat retention, as well as the sensitivity to insulin and leptin in a cell-specific manner. Together, the results suggest that GH acts in concert with other "gestational hormones" to prepare the maternal organism for the metabolic demands of the offspring.

Optimized fasting and OGTT-based simple surrogate methods for assessing insulin sensitivity.

AIMS: Simple surrogate indices of insulin sensitivity have been conceived to deal with costly and complicated approaches, such as the hyperinsulinemic-euglycemic clamp; however, their use has not been widespread given their variabilities in different populations. In this paper, we present two simple surrogate indices, one that uses fasting glucose and insulin values and the other based on the values from the oral glucose tolerance test. MATERIALS AND METHODS: The proposed methods integrate easy-to-obtain anthropometric measures. Evolutionary algorithms were used to optimize the proposed methods by maximizing its correlation with the Stumvoll MCR method. RESULTS AND CONCLUSION: When the proposed indices were applied to three study groups (control subjects, metabolic syndrome, marathon runners), a reduction in the intergroup variability of the insulin sensitivity was obtained. Moreover, the proposed index based on the oral glucose tolerance test (OGTT), which considers the glucose metabolism process and the hepatic and peripheral insulin sensitivity, showed stronger correlations with the Stumvoll method and lower intergroup variability than the fasting one.

Microbiota determines insulin sensitivity in TLR2-KO mice.

INTRODUCTION: Environmental factors have a key role in the control of gut microbiota and obesity. TLR2 knockout (TLR2-/-) mice in some housing conditions are protected from diet-induced insulin resistance. However, in our housing conditions these animals are not protected from diet-induced insulin-resistance. AIM: The aim of the present study was to investigate the influence of our animal housing conditions on the gut microbiota, glucose tolerance and insulin sensitivity in TLR2-/- mice. MATERIAL AND METHODS: The microbiota was investigated by metagenomics, associated with hyperinsulinemic euglycemic clamp and GTT associated with insulin signaling through immunoblotting. RESULTS: The results showed that TLR2-/- mice in our housing conditions presented a phenotype of metabolic syndrome characterized by insulin resistance, glucose intolerance and increase in body weight. This phenotype was associated with differences in microbiota in TLR2-/- mice that showed a decrease in the Proteobacteria and Bacteroidetes phyla and an increase in the Firmicutesphylum, associated with and in increase in the Oscillospira and Ruminococcus genera. Furthermore there is also an increase in circulating LPS and subclinical inflammation in TLR2-/-. The molecular mechanism that account for insulin resistance was an activation of TLR4, associated with ER stress and JNK activation. The phenotype and metabolic behavior was reversed by antibiotic treatment and reproduced in WT mice by microbiota transplantation. CONCLUSIONS: Our data show, for the first time, that the intestinal microbiota can induce insulin resistance and obesity in an animal model that is genetically protected from these processes.

Dipeptidyl Peptidase 4 Activity Is Related to Body Composition, Measures of Adiposity, and Insulin Resistance in Subjects with Excessive Adiposity and Different Degrees of Glucose Tolerance.

BACKGROUND: The enzyme dipeptidyl peptidase 4 (DPP4) has been recently recognized as an adipo-myokine. However, studies that associate its constitutive activity with body composition, anthropometry, and insulin resistance (IR) are very scarce and included only healthy people. METHODS: First, we investigated the relationships of constitutive DPP4 activity, body composition (assessed by bioelectrical impedance analysis), and measures of adiposity and IR in fifty-two subjects of both sexes, 18-50 years, and BMI ≥25.0 kg/m2 who comprised three groups according to glucose tolerance. Additionally, we evaluated associations among DPP4 activity and adipokines, gut peptides, and biochemical variables at fasting and 30 and 60 min after a standardized meal intake. RESULTS: DPP4 activity was no different among the three groups. At fasting, pooled analysis showed it was positively correlated with measures of central adiposity, such as WC (P = 0.011) and WHR (P = 0.009), and with all measures of IR, but inversely related to indexes of general adiposity, such as fat mass percentage (P = 0.014) and BAI (P = 0.0003). DPP4 activity was also associated with lean mass (r = 0.57, P < 0.0001). After meal intake, DPP4 activity remained significantly associated with insulin, leptin, and resistin. In multiple regression analysis, BAI, WHR, percent lean mass, HOMA-IR, and leptin influenced DPP4 activity and explained approximately 26% of the variance on it. CONCLUSIONS: Constitutive DPP4 activity is positively associated with lean mass, central adiposity, and IR and negatively to general adiposity. Furthermore, it seems to be influenced by body composition and IR and could also be viewed as an adipo-myokine in subjects with excessive adiposity and different stages of glucose tolerance.

Sclareol-loaded lipid nanoparticles improved metabolic profile in obese mice.

Sclareol is a bioactive hydrophobic diterpene in the essential oil isolated from Salvia sclarea (Fam. Lamiaceae). Sclareol has been widely studied due to its anti-inflammatory and antioxidant effects. AIMS: The present study aimed to evaluate the effects of Sclareol in different formulations (solid lipid nanoparticle and free) on the metabolic profile of obese mice. MAIN METHODS: Swiss male mice were randomly divided into two groups: standard diet (STD) and high-fat diet (HFD). After obesity induction, each group was divided into three treatment groups: free Sclareol (Sc), Sclareol-loaded lipid nanoparticle (L-Sc) and blank lipid nanoparticle (L). Treatments were performed every day during 30 days. KEY FINDINGS: L-Sc improves obese mice metabolic profile by decreasing adiposity, ameliorating insulin sensitivity, glucose tolerance and increasing the HDL plasma levels. In addition, L-Sc decreased the expression of NF-KB, MCP-1 and SERBP-1. SIGNIFICANCE: The use of sclareol together with lipid nanocarriers may be promising for the treatment of metabolic disorders by reducing adipose tissue.